Tetracyclines, such as doxycycline, are used as broad spectrum antibiotics to treat various bacterial infections. Tetracyclines interfere with the protein synthesis of Gram positive and Gram-negative bacteria by preventing the binding of aminoacyl-tRNA to the ribosome. Their action is bacteriostatic (preventing growth of bacteria) rather than killing (bactericidal). The doses commonly used for doxycycline to achieve the antibiotic effect are 100 mg and 50 mg.
Doxycycline, as well as other tetracyclines, has other therapeutic uses in addition to its antibiotic properties. For example, doxycycline is known to inhibit the activity of collagen destruction enzymes such as collagenase, gelatinase, and elastase. Its collagenase inhibition activity has been used to treat periodontal disease.
Doxycycline can also inhibit lipase produced by the bacterium Propionibacterium acnes and thus reduces the availability of free fatty acids that are involved in inflammation. Doxycycline may also reduce inflammation by reducing cytokine levels so that the integrity of the follicular wall is preserved. Thus, doxycycline has the potential in treating skin diseases, such as acne.
While tetracyclines have proven to be very beneficial and successful antibiotics, this class of compounds suffers from a major drawback associated with administration. Namely, tetracycline antibiotics cause an undesirable degree of gastrointestinal irritation and nausea in subjects taking the medications.
The nausea associated with administration of many tetracyclic antibiotics results from the release of the tetracycline into the lumen of an individual's stomach after ingestion. Since many tetracycline antibiotics are formulated as immediate release tablets, such antibiotic formulations begin to release antibiotic immediately upon administration and release high concentrations of tetracycline upon entering the acidic environment of a patient's stomach. The high localized concentration of the antibiotic in the patient's stomach leads to irritation and nausea.
There have been attempts to provide delayed or extended release pharmaceutical formulations of tetracyclic antibiotics that do not release in an individual's stomach, but rather release in the colon. However, many of these formulations suffer from inadequate dissolution profiles that do not provide an effective dose of antibiotic at the desired concentration and for the desired period of release.
Thus, there is a great need in the art for the development of improved controlled release pharmaceutical formulations of tetracyclic antibiotics.
More particularly, there is a need in the art for controlled release doxycycline antibiotic formulations that provide clinically effective doses of doxycycline with reduced stomach irritation and nausea.